The present invention relates to a novel functional chitin/chitosan derivative, and more specifically relates to a chitosan derivative with improved solubility, gel forming ability and hydrogel forming ability due to the incorporation of a carbohydrate having a reducing terminal and/or a photo-reactive functional group and/or an amphipathic group.
The application of natural materials has been widely researched in the medical and cosmetic fields for their biocompatibility such as their histocompatibilities and biodegradability. In particular, various uses can be conceived by solidification or formation of insoluble hydrogels by means of chelating with salts or crosslinking reactions.
For example, in recent years, research relating to the function of carbohydrate chains has become more active, making it clear that they play a considerable role in cell adhesion and viral infection. The carbohydrates in mammals exist mostly as composites such as glycoproteins and glycolipids, with some of these carbohydrate chains contributing to specific functional expressions. For this reason, these types of substances containing carbohydrate chain are often biologically active, but in practice, present problems in terms of their handling and cost.
On the other hand, in plants and marine organisms, carbohydrate chains exist as macromolecular substances for the skeletal structures of the organisms. Cellulose, pectin, gum arabic, polygalactomannan, arginic acid and the like are contained in plants and algae, and are macromolecular substances with high viscosity capable of being cheaply mass-collected. Additionally, chitin/chitosans are widely distributed in the exoskeletons of insects and the shells of crustaceans such as crabs and lobsters, glucosamin which is the constituent carbohydrate thereof having the function of an elicitor for protecting against infection and decomposition.
Since these carbohydrates exist as polysaccharides having extremely high molecular weights and also have high viscosity, their application to medicine such as in wound dressings, artificial skin, implants used in oral surgery or plastic surgery, hemostatics and adhesives, or to cosmetics such as humectants has been considered, but their range of application is limited due to the difficulty of chemically modifying them with regard to solubility in solvents and the like in comparison to proteinous ingredients.
Chitin/chitosans, which are unique even among polysaccharides, contain amino groups as constituent carbohydrate units, so that their use in conjunction with chemical crosslinking agents such as isocyanates, aldehydes and carbodiimides in wound dressings, anti-adhesion materials and decomposing absorbents has been studied.
However, chitins are not soluble in water due to their crystallinity, which is based on hydrogen bonds, and must be decomposed to low-molecular weight substances by means of hydrolysis or partially deacetylated in order to prepare them to be suitable for application to a wide range of industrial fields including medicine. Additionally, chitosans with increased carbohydrate units with amino groups exposed by active deacetylation for the purposes of improving the physical properties of chitins are soluble in acidic solvents including dilute organic acids, but are still extremely thick, making them difficult to handle in wound dressings and biological adhesion which are required to be easily worked on the scene of medical treatment. Additionally, since the thick chitosan solution does not retain a physiological pH, it is difficult to freely add physiologically active reagents used for therapeutic purposes, and there is the problem of toxicity when used with free chemical crosslinking agents, thus limiting the possibilities of use in the field of health care including medicine.
Upon performing diligent research, the present inventors found that the above-mentioned problems could be overcome by binding a carbohydrate having a reducing terminal and/or a photo-reactive functional group and/or an amphipathic group such as a polyoxyalkylene alkyl ether or the like and/or a glycosaminoglycan to at least a portion of the amino groups or hydroxyl groups in the glucosamin units forming the chitin/chitosans having structures with at least partially deacetylated poly-N-acetylglucosamin, thus achieving the present invention.
Thus, the present invention offers a functional chitosan derivative incorporating, in at least a portion of the 2-position amino groups in the glucosamin units forming an at least partially deacetylated chitin/chitosan, a carbohydrate having a reducing terminal as a first functionalization and/or a photo-reactive functional group as a second functionalization and/or an amphipathic group as a third functionalization and a glycosaminoglycan as a fourth functionalization. Here, the amphipathic group as the third functionalization may be incorporated into at least a portion of the hydroxyl groups at the 3- and 6-positions of the glucosamin units or acetylglucosamin units forming the chitin/chitosans. The functional chitosan derivative of the present invention changes the pH-dependent water solubility originally held by chitosan by incorporating carbohydrate chains having reducing terminal, making it soluble in water in the physiological pH region, enables the chitin/chitosans to become insoluble self-crosslinked bodies by incorporating photo-reactive functional groups, enables an advantageous gel forming ability and high water content to be achieved by incorporating the amphipathic groups and confers an anti-adhesion ability by incorporating the glycosaminoglycan.
By binding carbohydrates and/or photo-reactive crosslinking groups and/or amphipathic groups to chitin/chitosans which are known to have tissue compatibility and wound healing effects, the chitosan derivative of the present invention is given water solubility in the physiological pH region, self-crosslinking by means of covalent bonds (hardening) by means of a photoreaction or an insoluble gel forming ability based on intermolecular interactions, thus not only making it safely compatible with biological tissue in the physiological pH range, but also enabling the formation of a hydrogel having an arbitrary strength and water content. Furthermore, the hydrogel formed using the chitosan derivative of the present invention does not use free chemical crosslinking agents and is therefore safe, and is able to bind various physiologically active substances due to its high water content and water retention, having a wide range of uses as a healthcare material in the medical field as wound dressings, anti-adhesion materials, hemostatics, sealants for body fluids or gases, clathrates for drug delivery and encapsulating agents for cells, and also in the cosmetic field as protecting materials for the skin and hair.